Previous efforts to identify biological correlates of anti-depressant response in bipolar disorder have yielded only modest success. The degree to which depression arises from serotonergic or other neurotransmitter abnormalities remains an unsolved question. Moreover, standard anti-depressants may be less effective for bipolar than unipolar depression and pose unique risks for inducing mania or cycle acceleration. Therefore, a compelling need exists to develop new methodologies to better anticipate treatment outcomes. The focus of this Career Development Award is to provide a translational research and training experience for the P.I. in applications of psychiatric genetics to clinically-based studies of psychopathology and treatment outcome in bipolar illness. As a model for this type of research, pharmacogenetic correlates of anti-depressant response, focusing on serotonin system candidate gene polymorphisms, will be examined in a family-based cohort. While preliminary studies have identified candidate genes with polymorphisms of significance to psychopathology, or psychotropic drug action, pharmacogenetic applications ti bipolar disorder remain largely unexplored. The proposed core research project will be an ancillary study to the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), an NIMH-sponsored multi-clinical trial. DNA samples will initially be obtained from a minimum of 100 depressed probands and family members; probands already optimized on valproate or lithium will undergo a 6-week trial of a serotonin reuptake inhibitor. In later years of the Award period, family-based genotype and SSRI antidepressant response data will be added from several hundred additional bipolar probands at collaborative research sites. Antidepressant responsivity will be analyzed relative to allele frequencies of 4 serotonin-related polymorphic candidate genes of known functional significance. Multivariate models will be developed to assess the relative statistical contribution of pharmacogenetic polymorphisms added to clinical factors potentially associated with treatment response. The primary aim of the career development plan is for the P.I. to acquire expertise in human genetics and candidate gene polymorphism analyses in order to inform future clinical studies of psychotropic drug response and other aspects of psychopathology that may represent phenotypes of bipolar disorder.